This randomized phase III clinical trial studies chemotherapy with or without trastuzumab after surgery to see how well they work in treating women with invasive breast cancer. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) and giving chemotherapy after surgery may kill more tumor cells. Monoclonal antibodies, such as trastuzumab, can block cancer growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether combination chemotherapy is more effective with trastuzumab in treating breast cancer.

The interaction between treatment effect and HER2 mRNA level will be evaluated in the proportional hazards model, which would include an indicator for treatment group and the HER2 mRNA level as a continuous variable, and the corresponding interaction term. The log-hazard ratio plot for the interaction term with 95% confidence intervals will be used to determine the cut-off of the HER2 mRNA level that would determine a subset of the patients who would benefit from the adjuvant trastuzumab therapy.

DFS-DCIS [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]

DRFI [ Time Frame: From randomization until the first diagnosis of distant metastasis or death from breast cancer, assessed up to 10 years ] [ Designated as safety issue: No ]

Fcgamma receptor polymorphism [ Time Frame: From baseline to up to 24 months ] [ Designated as safety issue: No ]

The polymorphism of the Fcgamma 158 receptor gene will be dichotomized as V/V (valine) vs. other genotypes and the polymorphism of the Fcgamma 131 receptor gene will be dichotomized as H/H (histidine) vs. other genotypes to evaluate an interaction between treatment group and Fcgamma polymorphism. The Kaplan-Meier method105 will be used to estimate the distribution of the primary endpoints stratified by the dichotomized subgroups, and the log-rank test106 will be used to statistically compare the time-to-event distributions.

Incidence of adverse events using the National Cancer Institute CTCAE v4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]

The frequency and severity of adverse events will be graded.

OS [ Time Frame: From randomization to death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]

RFI [ Time Frame: From randomization until invasive local, regional, or distant recurrence, or death from breast cancer, assessed up to 10 years ] [ Designated as safety issue: No ]

Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast cancer; (comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer)

Women of reproductive potential must agree to use an effective non-hormonal method of contraception (for example condoms, some intrauterine devices, diaphragms, tubal ligation, vasectomized partner, or abstinence) during therapy and for at least 6 months (Arm 1 patients) and for at least 7 months (Arm 2 patients) after the last dose of study therapy (chemotherapy or trastuzumab)

Submission of tumor samples from the breast surgery is required for all patients; therefore, the local pathology department policy regarding release of tumor samples must be considered in the screening process; patients whose tumor samples are located in a pathology department that by policy will not submit any samples for research purposes should not be approached for participation in the B-47 trial

The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines

HER2 status of the primary tumor must be evaluated prior to randomization; all testing performed must indicate that the tumor is HER2-low as defined below

IHC must be performed and the IHC staining results must indicate a score of 1+ (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be performed and must indicate that the tumor is HER2-low as described below)

If ISH testing is performed, test results must be as follows and IHC must be 1+ or 2+: the ratio of HER2 to chromosome enumeration probe 17 (CEP17) must be < 2.0 or, if a ratio was not performed, the HER2 gene copy number must be < 4 per nucleus

Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+ to 2+, the higher intensity score in the range should be used to determine eligibility

The patient must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy); (patients who have had a nipple-sparing mastectomy are eligible)

For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist; if pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins; if tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible; (patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection)

For patients who undergo mastectomy, margins must be free of gross residual tumor; (patients with microscopic positive margins are eligible as long as post-mastectomy radiation therapy [RT] of the chest wall will be administered)

The patient must have completed one of the procedures for evaluation of pathologic nodal status listed below:

Sentinel lymphadenectomy alone:

If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b

If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the nodal involvement must be limited to 1 or 2 positive nodes

Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or

Axillary lymphadenectomy with or without SN isolation procedures

The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days

The patient must have ER analysis performed on the primary tumor prior to randomization; if ER analysis is negative, then PgR analysis must also be performed (either the core biopsy or surgical resection specimen can be used for ER/PgR testing); patients with a primary tumor that is hormone receptor-positive or receptor-negative are eligible

Absolute neutrophil count (ANC) must be >= 1,200/mm^3

Platelet count must be >= 100,000/mm^3

Hemoglobin must be >= 10 g/dL

Total bilirubin must be =< upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert disease or similar syndrome involving slow conjugation of bilirubin

Alkaline phosphatase must be =< 2.5 x ULN for the lab

Aspartate aminotransferase (AST) must be =< 1.5 x ULN for the lab (if alanine aminotransferase [ALT] is performed instead of AST [per institution's standard practice], the alanine aminotransferase [ALT] value must be =< 1.5 x ULN; if both were performed, the AST must be =< 1.5 x ULN)

Alkaline phosphatase and AST may not both be > the ULN

Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]-CT, or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the above requirements are met

Patients with alkaline phosphatase that is > ULN but =< 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease

The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be =< ULN for the lab

Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days prior to randomization; LVEF assessment performed by 2-dimensional (D) echocardiogram is preferred, however, multi-gated acquisition (MUGA) scan maybe substituted based on institutional preferences

For patients who will receive the TC chemotherapy regimen, the LVEF must be >= 50% regardless of the cardiac imaging facility's lower limit of normal

For patients who will receive the AC-->WP chemotherapy regimen, the LVEF must be >= 55% regardless of the cardiac imaging facility's lower limit of normal

NOTE: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments, it is critical that this baseline study be an accurate assessment; if the baseline LVEF is > 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and repeat the test if the accuracy is uncertain

Exclusion Criteria:

Primary tumor with any of the following HER2 testing results:

IHC staining intensity:

0 on all evaluations of specimens

3+ on evaluation of any specimen

ISH with a ratio of HER2 to CEP17 >= 2.0 on evaluation of any specimen

ISH result indicating HER2 gene copy number >= 4 per nucleus on evaluation of any specimen

T4 tumors including inflammatory breast cancer

Definitive clinical or radiologic evidence of metastatic disease

NOTE: Chest imaging (mandatory for all patients) and other imaging (if required) must have been performed within 90 days prior to randomization

Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS; (patients with synchronous or previous ipsilateral LCIS are eligible)

History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization

Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy

Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization

Whole-breast RT prior to randomization or partial-breast RT that cannot be completed on or before the date of randomization

Continued endocrine therapy such as raloxifene or tamoxifen (or other selective estrogen receptor modulator [SERM]) or an aromatase inhibitor; patients are eligible if these medications are discontinued prior to randomization

Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy; patients are eligible if these medications are discontinued prior to randomization

Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens; this includes but is not confined to:

Active cardiac disease:

Angina pectoris that requires the current use of anti-anginal medication

Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor EL

Pregnancy or lactation at the time of study entry; (Note: pregnancy testing must be performed within 2 weeks prior to randomization according to institutional standards for women of childbearing potential)

Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up

Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements

Use of any investigational product within 30 days prior to randomization

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01275677